MMP‐9 deletion improves vascular permeability and angiogenesis in aging mice (880.8)

Abstract

Aging is a major risk factor for cardiac morbidity and mortality. Increasing age associates with increased MMP‐9 expression, increased ECM degradation, and a decline in cardiac function. Previously, we demonstrated that wild type (WT) mice >18 months of age show impaired diastolic function, which was attenuated by MMP‐9 deletion. To investigate the changes that occur before cardiac dysfunction develops, we examined 6‐9 and 15‐18 month old (mo) WT and MMP‐9 null (Null) mice. All groups showed similar cardiac function by echocardiography and Doppler, indicating that functional changes in the left ventricle (LV) had not yet developed. Plasma proteomic profiling and LV tissue analysis revealed age‐associated increases of von Willibrand factor and VEGF in WT mice, which were enhanced in Null mice, suggesting that aging and MMP‐9 deletion stimulates angiogenesis. However, the number of vessels evidenced by GSL‐1 staining and protein expression was increased only in the 15‐18 mo Null LV. To evaluate vascular function, we injected WT and Null mice with FITC labeled dextran (70 kDa). The 15‐18 WT mo mice showed increased vascular permeability compared to the younger WT controls, which was significantly attenuated in Null mice. Our findings revealed that the age‐associated increase in MMP‐9 links with increased vascular permeability, which may contribute to the development of diastolic dysfunction.Grant Funding Source: Supported by SC2 HL101430,HL095852,HHSN 268201000036C(N01‐HV‐00244),R01HL075360,HL05197,5I01BX000505